Arginine is considered to be a semi-essential amino acid in certain mammals, i.e., while arginine can be synthesized by these mammals, it cannot be synthesized at a rate sufficient to meet the demands of normal growth. In humans, arginine is not growth-limiting and therefore is a non-essential amino acid.
The synthetic pathway for arginine commences with ornithine. Ornithine is combined with carbamyl phosphate to produce citrulline, which in turn is combined with aspartate, in the presence of adenosine triphosphate (ATP), to produce argininosuccinate. In the final step, fumarate is split from argininosuccinate, to produce arginine. The degradative pathway for arginine is by the hydrolytic action of arginase, to produce ornithine and urea. All of the reactions described above form the urea cycle.
Arginine's best-studied functions are in the urea cycle and as an essential amino acid for the synthesis of proteins. However, other functions for arginine have been described. Of particular interest is the effect of arginine and its metabolic precursor, ornithine, on the immune system of immunosuppressed or immune-impaired animals. Since arginine is a component of proteins, it is present in a normal diet. However, ornithine is not a component of proteins and, as a result, it is not present, at significant levels, in a normal diet.
The immune system of mammals is comprised of two kinds of effector mechanisms; the first mechanism is mediated by antibodies and is called "humoral immunity"; the second mechanism is mediated by cells and is called "cell-mediated immunity" (CMI). Most immune responses involve the activity and interplay of both the humoral and the cell-mediated branches of the immune system.
Antibodies, which are molecules that are able to specifically recognize and bind antigens, are found in the blood and lymph and are synthesized in a subset of lymphocytes called "B lymphocytes" or "B cells." CMI, on the other hand, derives its specificity from a subset of lymphocytes called "T lymphocytes" or "T cells."
The development of a normal CMI response requires a functional thymus. In humans, as well as in other mammals, the thymus reaches its maximal size at about the age of puberty. Thereafter, it shrinks or involutes, and much of its architecture is replaced by fatty tissue. In old age, the thymus is reduced to a tiny, fatty rudiment. However, despite the age-related involution, aged thymuses retain some function. Stress is one factor which results in thymus involution. The probable mechanism of stress involution of the thymus, where disease or other stresses lead to rapid shrinking of the thymus, is the stress-triggered releases of corticosteroids from the adrenal cortices. The thymus is very sensitive to this group of hormones (corticosteroids), and injection of a corticosteroid, such as cortisol, leads to rapid (within hours) involution of the thymus of experimental animals.
The main function of the thymus in CMI is to produce mature T lymphocytes, the cells that carry out CMI. T lymphocytes are made up of a number of subsets of lymphocytes which have specialized functions. Of particular interest are two subsets of lymphocytes called "T suppressor cells" (Ts) and "T helper cells" (Th). The Ts cell subsets are responsible for suppression of both humoral immune reactions and CMI reactions. Ts cells differ from the other subsets of T cells in being able to bind to soluble antigen. The Th subsets are required to assist B cells to mount a humoral response to certain antigens.
The ability of an animal to mount an immune response, both humoral and cell-mediated, is called immunocompetence and is critical for fighting off infection. However, under certain conditions, such as trauma, surgery, certain viral infections, and cancer, an animal's ability to fight infection is impaired (an impaired immune response is also called immunosuppression) and sepsis results.
A measure of the ability of an immune system to respond normally can be made by evaluating the ratio of Th cells to Ts cells in the blood. For example, a Th/Ts ratio of less than about 1 is considered to be an indicator of an impaired immune response in humans.
The activity of T lymphocytes in vivo has been found to correlate with their in vitro response to mitogens, which are a variety of chemical substances which bind to the surface of lymphocytes and, in doing so, stimulate them to undergo mitosis. Mitosis is an important indicator of immune function, since T cells have to replicate (a process known as clonal expansion) in order to carry out their immune functions. A measure of the ability of cells to undergo mitosis is the stimulation index, which is the ratio of the mean number of cells in the presence of a mitogen to the mean number of control, or unstimulated, cells. Commonly, the number of cells is estimated by labeling them with radio-labeled thymidine and measuring counts per minute (as an assay of DNA content, which is directly correlated with cell numbers). Stimulation index is therefore calculated by the ratio of counts per minute of mitogen-stimulated cells divided by counts per minute of unstimulated cells. A low stimulation index is another indicator of an impaired immune response. For example, when the stimulation index is reduced to below approximately 50% of its normal value, the immune response can be considered to be impaired.
Several lymphocyte mitogens are plant-derived glycoproteins (lectins) that bind specifically to certain sugar residues of glycoproteins on the cell surface. Two such lectins are Phytohemagglutin (PHA) and Concanavalin A (ConA). PHA, extracted from the red kidney bean, binds to both B and T lymphocytes. However, it only stimulates mitosis in mature cells. ConA, extracted from the jack bean, has a strong mitogenic effect on T cells, immature as well as mature, but not on B cells.
Dietary arginine supplementation has been used to treat rats and mice that have been subjected to trauma. In such animals, arginine has been observed to produce an increase in thymic weight, an increase in the number of lymphocytes present in the thymus, an increase in the response of lymphocytes to mitogens, a positive effect on virus-induced tumors where the virus was thymolytic and the subsequent damage to the thymus allowed for the initial tumor expression, an increase in weight gain, and enhancement of wound healing. Citrulline, a metabolic precursor of arginine, can replace arginine for growth requirements, but has been found to have no detectable effect on thymus function, i.e., has no thymotropic action. Ornithine, another metabolic precursor of arginine, exhibits the thymotropic effect of arginine without being able to replace it for growth requirements.
It has been suggested that the positive effects of arginine on wound healing are mediated via an intact thymus, and the beneficial effects of supplemental arginine in animal tumor models appear to correlate with its thymotropic effect. The positive effect of arginine on these animals' immune systems has been proposed to be due, in part, to arginine's well-known secretory-inducing activity on pituitary and pancreatic hormones, particularly on growth hormone. Growth hormone also leads to an increase in thymic weight and, therefore, cell-mediated immunity.
Although there have been major advances in the care of severely ill patients, such as new antibiotics, nutritional support, and developments in critical-care medicine, many ill patients still die due to sepsis. Such sepsis occurs as a result of an impaired immune response that is either pre-existing or which occurs as a result of the illness that initially caused the patient to be admitted to the hospital. The most common causes of such an impaired immune response in severely ill patients are trauma, major surgical procedures, malnutrition, cancer, old age, and infection with HIV (AIDS) virus.
Previously, nutritional supplementation of severely ill patients has been used to maintain a patient's body protein stores in an attempt to counteract the protein breakdown (catabolism) that such patients suffer. Although this nutritional supplementation is often successful in reversing the catabolic process and can even stimulate some anabolic processes, such as wound healing, in many cases, it has not been shown to reverse the impaired immune response exhibited by these patients. These patients remain at risk of sepsis and death, in spite of nutritional supplementation. Therefore, a safe and effective nutritional means of restoring the immune response would be beneficial to the long-term survival of these severely ill patients.